Manufacture of basic bismuth salts of aryl-arsinic acids



Patented May 15, 1928.

UNITED STATES PATENTOFFICE.

RALPH WILLIAM EWART STICKINGS, OF SURREY, ENGLAND, ASSIGNOR T0 MAY &

' BAKER LIMITED, OF LONDON, ENGLAND, A BRITISH COMPANY.

MANUFACTURE OF BASIC BISMU'TH SALTS 0F AR-YL-ARSINIG ACIDS.

N-o Drawing. Application filed December2, 1926, Serial No. 152,307, and in Great Britain December 5, 1925.

The present invention is for the manufacture of basic bismuth salts of aryl-arsinic acids, and has particular reference to the manufacture of the bismuth salt of N- phenyl-glycinamide-p-arsinic acid.

The basic bismuth salts of aryl-arsinic acids possess therapeutic properties, and, appropriately prepared, are suitable for injection; and it has been found that in such salts the therapeutic properties of both bismuth and arsenic are advantageously combined, the toxicity of the products being generally of a low order.

It is known that if concentrated aqueous solutions of the sodium salt of l-oxy-3-acetylaminophenyl-arsinic acid and of sodiumpotassium-bismuth tartrate are broughttogether, the basic bismuth salt of the arsinic acid is formed as a precipitate. The sodium potassium-bismuth tartrate may be replaced by other salts of bismuth, and the arsinic acid mentioned by other aryl-arsinic acids, which may be in the form of salts of other bases than sodium.

For the manufacture of these bismuth salts, especially for therapeutic purposes, the method has a number of disadvantages. If solutions of equimolecular' proportions of the aforesaid type of reagents be mixed together at ordinary temperature, precipitation of the new compound is slow and incomplete, and the yield poor. With application of heat, precipitation is expedited, but without the production of a satisfactory yield. If the attempt be made to correct incomplete precipitation by leavingthe reaction mixture to stand, the precipitate frequently appears in the form of a gel, which is difficult to wash, and even in these circumstances, an' unsatisfactory yield of the new salt is obtained.

The process of the present invention consists in an adaptation of the aforesaid process to the manufacture of basic bismuth salts of the type described, whereby the salts are obtained in substantial yield, and in a form readily adaptable to purification and to the preparation of therapeutic solutions.

According to the present invent-ion, the manufacture of basic bismuth salts of arylarsinic acids is characterized by precipitating the solution of a bismuth salt with the solution of a salt of an aryl-arsinic acid un der application of heat in presence of a con siderable excess of the aryl-arsinic acid salt.

The preferred type of bismuth salts with which to effect precipitation are salts of hydroxy-polybasic acids, of which tartaric acid is an example, such salts being conveniently employed in the form ofthe soluble double salts with such acids of bismuth and alkaline bases, as, for example, sodium-, or sodiumpotassium-, bismuth tartrate.

Thus, the solution of a soluble bismuthyl salt of a hydroxy-polybasic acid, such as tartaric acid, may be added to the solution containing a substantial excess over the molecular equivalent of a soluble salt of an aryl-arsinic acid. For example, an aqueous solution of an alkali bismuthyl tartrate, such as sodium bismuthyl tartrate, may be treated with an aqueous solution of the sodium derivative of the aryl-arsinic acid in considerable excess over the quantity theoretically equivalent to the bismuthyl salt.

The precipitated bismuth oxy-saltof the arsinie acid is washed and dried, preferably at a low temperature. It is advisable in most cases to separate the precipitate from the reaction liquor without undue delay in order to avoid undesirable change in condition of the product.

A substantial excess of the salt of the aryl-arsinic acid is used but the actual degree of excess is necessarily a factor which must be adjusted according to the particular reagents employed. Examples of appropriate proportions are given hereafter, and,

as a general guide, it may be said that the excess should not be below about 25 per cent, and may be as high as 80 per cent. As in the case of the temperature factor, the PHI'.

pose of the excess is to obtain a reaction product in good yield and at the same time in a satisfactory form for washing and subsequent use, and the adjustment of the relative proportions of the reagents in any given case is made with this object in view.

The reacting substances may be mixed together at the ordinary temperature, and the temperature then appropriately raisedand maintained as may be necessary to promote the reaction and the separation of a fine washable precipitate. If the temperature be too low, the precipitate tends to assume the form of avgel, while if the temperature at least 30 C.

be too high, the precipitate may separate in too line a condition for satisfactory handlingf For example, in the caseof sodiump-arsanilate and sodium-t-oXy-3-acety1aininophenyl-arsinate, a temperature of 100 C. produces a precipitate so finely sub-divided as tomake Washing diflicult and protracted. The generally )referred temperature is one about C. Tendency to gel formation is generally observable up to a temperature of As Will be appreciated, a definite rule to meet all cases cannot be laid down as to'the degree of excess and the temperature; but the necessary adjustn'ient of these factors is attainable when it is borne in mind that the object in View is to produce a fine precipitate, which is yet sul'liciently. susceptible with reasonable facility to purification by Wash-- ing; and the limits given in illustration of the variation which may be made in the factors in question are those which have been found to be generally applicable with satis-. factory results.

Asstated, the precipitate should be separated Without delay, for a greater or less tendency to gel formation is displayed according to the length of time the reactionmixture is allowed to stand.

limample 1.

.phenyl-glycinami de-p-arsinic acid. The graphical formula for this salt is NHoHiooNm The excess of sodium-N-phenyl-glycinalnlde-p-arsinate in this casewas about25 percent.

Example 11.

To a solution of 50 grains of sodium bismuthyl tartrate in 50 cc. of Water Was-added a solution of 50 grams of sodium-p-amium phenylarsiuate in 100 cc. of hot Water. The resulting mixture Was heated at 70 C. for fifteen minutes and the Whiteprecipitato filteredoff, Washed With Water and dried. The product was the bisniuthyl salt of pand maintained at water, and dried.

basic b smuth salt of 2-oXy-5-acetylaminophenylarsnnc acid. The grapl'ucal formula aminophenylarsinic acid. formula for this salt is 'As-OH l o-Buo'mi The graphical t In this instance the sodiu nep-aminophenylarslnate was in an excess of about per cent. 4 l

lfwwntple I I] To a solution of gra1'ns of sodium lnsinuthyl tartrate in 100 cc. Water was added a solution of 100 grams of sodmnrtl:

acetylamino-et-oxyphenylarsiuate in 100 cc.

of hot water. The resulting n'iixture was heated at 70 C for 15 minutes, the yellow precipitate filtered off, washed with distilled water, and dried; The product was the basic bismuth salt of 3-acetylan'iinol-oXypl'ienyl-arsinic acid. The graphical formula for this salt is y Ase-on o q auou Nnoooni In this-casethe sodium 3-acetylamino-41 onyphehylarsinate was in an excessof about 60 per cent. l

To .a. solution of 100 grams of sodium bismuthyl,tartrate in 100 cc. of WaterWas added a solution of 100 grams of sodium 2 olxy}5acetylaminophenylarsinate in 100 cc. hot water. The "resulting mixture was heatedfat 70 C. fo'r lan'iinutes, the yellow precipitate filtered ol'l',.wasl'ied Withdistilled The product was the for th is 1 salt is Inthis case the sodium-2-oXy-5-acetylamlnophenylarslnate Was in an, excess of about 60percent.-

1. The manufacture of basic bismuth salts of aryl-arsinic acids,which comprises pre loo cipitating a solution of a bismuth salt with the solutionof a salt of an aryl-arsinic acid underapplication of heat in presence of a consnllcrable excess of the aryl-arsinic acid salt.

2. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of the bismuth salt of an hydroxy-polybasic acid with the solution of a salt of an aryl-arsinic acid under application of heat in presence of a considerable excess of the aryl-arsinic acid salt.

3. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of a double bismuthalkali salt of an hydroxy-polybasic acid with the solution of a salt of an aryl-arsinic acid under application of heat in presence of a considerable excess of the aryl-arsinic acid salt.

4. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of a bismuth salt with the solution of a salt of a substituted-arylarsinic acid under application of heat in presence of a considerable excess of the arylarsinic acid salt.

5. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of an alkali-bismuthyl tartrate with the solution of a salt of an aryl-arsinic acid under application of heat in presence of a considerable excess of the aryl-arsinic acid salt.

6. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of sodium bismuthyl tartrate with the solution of a salt of an aryl-arsinic acid in considerable excess under application of heat.

7. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of a bismuth salt with the solution of a salt of an a-ryl-arsinic acid in considerable excess at a temperature above about 30 C. and below about 100 C.

8. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises pre cipitating a solution of sodium bismuthyl tartrate with the solution of a salt of an aryl-arsinic acid in considerable excess at a temperature above about 80 C. and below about 100 C.

9. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of sodium bismuthyl tartrate with the solution of a salt of an aryl-arsinic acid in considerable excess at a temperature of about 70 C.

10. The manufacture of basic bismuth salts of aryl-arsinicacids, which comprises precipitating a solution of a bismuth salt under application of heat with the solution of asalt of an aryl-arsinic acid in a minimum excess of substantially 25 per cent over the quantity equivalent to the mother-bismuth salt.

11. The manufacture of a basic bismuth salt of N-phenyl-glycinamide-p-arsinic acid, which comprises precipitating a solution of a bismuth salt with the solution of a salt of said acid in considerable excess under application of heat.

12. The manufacture of a basic bismuth salt of N-phenyl-glycinamide-p-arsinic acid which comprises precipitating the solution of an alkali bismuthyl tartrate with an alkali salt of N-phenyl-glycinamide-p-arsinic acid in an excess of at least 25 per cent over the quantity. equivalent to the mother-bismuth salt under application of heat.

13. The manufacture of a basic bismuth salt of N-phenyl-glycinamide-p-arsinic acid, which comprises precipitating a solution of an alkali bismuthyl tartrate with an alkali salt of said acid in an excess of at least 25 per cent over the quantity equivalent to the the mother-bismuth salt at a temperature of substantially 7 0 C. r

14. The manufacture of a basic bismuth salt of N-phenyl-glycinamide-p-arsinic acid,

which comprises precipitating a solution of sodium bismuthyl tartrate with the sodium salt of said acid in an excess of at least 25 per cent over the quantity equivalent to the mother-bismuth salt at a temperature of substantially 70 C.

15. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating the solution of a bismuth salt with the solution of a salt of an aryl-arsinic acid under applicat-ion'of heat in presence of a considerable excess of the aryl-arsinic acid salt, and separating the precipitated bismuth salt from the reaction liquor as soon as precipitation is complete.

16. The manufacture of basic bismuth salts of aryl-arsinic acids, which comprises precipitating a solution of a bismuth salt under application of heat with the salt of an a-ryl-arsinic acid in an excess of substantially 25 to 80 per cent over the quantity equivalent to the mother-bismuth salt.

In testimony whereof I aflix my signature.

RALPH WILLIAM EWART STICKINGS. 

